Thinking Big to Unravel the Genetics of Cancer

Acute myeloid leukemia under the microscope

As a graduate student, Kenan Onel, MD, PhD, feared the fate of the medieval "scholastic" philosophers who contemplated arcane conundrums like "the number of angels who could dance on the head of a pin."

"I was concerned about spending my life studying something so small it was irrelevant," said Onel.

He needn't have worried. In 2009, Onel, associate professor of pediatrics at the University of Chicago Medicine, led a team that identified genetic mutations associated with therapy-related acute myeloid leukemia (t-AML), a deadly cancer affecting thousands of people each year.

This leukemia occurs in patients who have previously beaten cancer. It is caused by the very treatment that drove their earlier recovery. Average life expectancy from diagnosis is less than 10 months.

Comparing DNA from 80 t-AML patients with that of 150 healthy controls, Onel and his colleagues found genetic variations linked to t-AML in patients with chromosomal changes associated with certain chemotherapy drugs.

Last year, he led a study, co-authored by University of Chicago graduate student Timothy Best and published in Nature Medicine, that employed a similar approach to identifying genetic variants associated with susceptibility to radiation therapy-induced second cancer among survivors of Hodgkin lymphoma.

They hope ultimately to identify drug targets and biomarkers for genetic susceptibility. Screening for the latter could have a far-reaching impact in post-Hodgkin second cancers, in particular; Hodgkin is among the easiest cancers to treat, giving physicians latitude to modify their treatment in some cases in order to reduce the risk to patients of developing a second cancer.

"As we have more success treating cancer, more people are at risk for these [second cancers]," said Michelle M. Le Beau, PhD, Arthur and Marian Edelstein Professor of Medicine and director of the University of Chicago Medicine Comprehensive Cancer Center.

"Identifying them is critical. These are aggressive diseases that account for a significant proportion of overall cancer deaths," said Le Beau, who is a close collaborator on the t-AML project, along with Richard A. Larson, MD, director of the hematologic malignancies program.

They also represent potent "model" systems through which to study cancer more broadly. "Years of epidemiologic research demonstrate conclusively these cancers are 100 percent caused by therapeutic exposure," said Onel. "They offer an extreme surrogate for the environmental exposures that occur in the natural world. This gives us insights into the general mechanisms behind cancer."

His team, Le Beau, Larson and many others, are working closely together to follow up the t-AML study, Onel said.

The mapping of the human genome in 2003 raised hopes of a "genomic revolution" in which sequencing would illuminate the genetic profiles of different diseases, lighting the way to new, targeted therapies. Genome wide association studies (GWAS), whereby a person's DNA is scoured to identify genetic variations associated with particular conditions, were viewed as a key way to realize this vision. But while they have identified numerous genetic mutations linked to diseases, these associations have mostly been so weak as to be "meaningless," said Onel. The genomic revolution has been delayed.

"The failure of most GWAS stem from their inability to adequately characterize environmental exposures," said Best, a graduate student in the University's Committee on Cancer Biology and a member of Onel's lab.

By focusing on t-AML and post-Hodgkin second cancer, Onel and his team introduced a more nuanced approach. They could account not only for genetic factors, but also for environmental variables (something GWAS have hitherto been largely blind to) and the interplay between them -- so-called "exposure-driven genetic susceptibility." Using GWAS, Onel set out to capture the nature and nurture of cancer.

In the Nature Medicine study, his team analyzed a pool of patients exposed to a single, known toxin, but in which only a subset developed cancer as a result. They could ask the question, what was genetically different in the cohort that developed cancer versus the one that stayed healthy?

"When you take strong potentiating events like chemo- or radiotherapy, you can pick out the genetic variants that play a strong role as a consequence," said Le Beau. "It's a unique approach that maximizes the power of GWAS at a time when people have become a little disenchanted with them."

It also advances an emerging view of cancer that is moving away from segmenting it by organ of origin toward identifying cellular mechanisms that may be common across ostensibly disparate cancers. Onel and his team note in Nature Medicine that the variants linked to susceptibility to post-Hodgkin second cancer affect PRDM1, a gene "frequently lost in many cancer types," for example. "Although cancer is complex, we're seeing it converge on the same cellular pathways," said Le Beau. "Drugs you identify for one disease may be effective in others."

Onel, who received his MD and PhD at Cornell University, had long aspired to attempt this sort of inquiry, but it was only when he arrived at the University of Chicago in 2004 that he found the resources to put his ideas into action. The University had painstakingly collected records of patients with t-AML, providing the raw material and impetus for his work. "It enabled us to do an experiment no one else could do," he said.

For his part, Onel brought an irrepressible spirit, and a flair for collaboration and connecting the dots, say colleagues and students.

"Ken thinks big and is extremely upbeat and positive in his approach to science," said Le Beau.

"All our projects have multiple collaborators and the need to get samples from different labs," said Mark Sasaki, PhD'07, whom Onel helped advise toward his doctorate in cancer biology and who recently joined Onel's lab as a postdoctoral fellow in genomics, having completed a postdoctoral fellowship in neuroscience at the University of Oregon. "A lot of our ability to do them is Ken going to meetings, Ken talking to people. He really pushes the interdisciplinary aspect."

In his latest venture, Onel has joined forces with Professor of Ecology and Evolution Chung-I Wu, PhD, in an intriguing and potentially groundbreaking study that is applying principles from evolutionary biology to cancer. By conceiving of cancer cells as analogous to any other population of organisms in facing selective pressures (competition between cells and the depredations of the body's natural defense mechanisms, for example) that shape their evolution, they hope to identify the genes that drive cancer development with greater precision.

"It's an evolutionist meets a cancer biologist," said Wu. "I've learned so much from him and I hope he finds my perspective useful."

To Onel, it's another piece of a complex puzzle.

"Again, it is big picture," he said. "It is about how we get cancer; why some people get it and others don't. The t-AML studies gave us information about genetic predisposition in the context of environmental exposure; the evolution stuff will enable us to study the transition from normal to cancer. And ultimately they're going to connect."

This story originally ran in the Summer 2012 issue of Medicine on the Midway, a publication for friends, alumni and faculty of the University of Chicago Medicine, the University of Chicago Division of Biological Sciences Division and the Pritzker School of Medicine.
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